Immunopathology II Flashcards
What is an allergy?
Hypersensitivity disorder of the immune system -> reaction to normally harmless environmental substances
What is the subdivision of hypersensitivity? (2)
- Allergic hypersensitivity = immunologically mediated
- Non-allergic hypersensitivity = non-immunologically mediated
What are the types of immunological hypersensitivity reactions?
- Type I = IgE-mediated degranulation of mast cells
- IgG-mediated response to antigens presented on the cell surface
- IgG-mediated response to deposition of immune complexes
- Type IV = T-cell mediated response
Which further subdivision can be identified within type I allergies? (2)
- Atopic = genetic predisposition
- Non-atopic
Which type I allergies are often not atopic? (3)
- Insect venom
- Helminths
- Drugs
Which type I allergies are often atopic?
- Asthma
- Rhinoconjunctivitis
- Urticaria
In which cases is IgE elevated in the serum? (3)
- Physiological response to parasitic infections
- Hyper-IgE-syndrome
- IgE-mediated diseases
Are mast cells found in circulation?
No, only in tissue
Which processes are triggered by mast cell degranulation? (3)
- Contraction of smooth muscle
- Vasodilation and increased vascular permeability
- Irritation of mucous membranes
Which kind of T-cell response is an IgE-mediated allergic reaction?
Th2
What is the role of Th2 cells in IgE-mediated allergy? (3)
- Induces class switching of B-cells to IgE
- Attracts eosinophils to the site of allergen exposure
- Produces cytokines upon allergen exposure
What is the difference between sensitization to an allergen and allergy?
Sensitization = IgE-production
Allergy = IgE-mediated clinical manifestation upon contact with allergen
What is needed for an allergy to develop?
Repeated exposure to allergen
What is the hygiene hypothesis?
Insufficient exposure to infectious pressures during childhood leads to a disrupted balance between Th1/Th2-responses
What is an important characteristic of type I allergens? Why do type I allergens have this property? (3)
Capable of penetrating epithelial barriers
1. Low molecular weight
2. Good solubility in aqueous milieu
3. Enzymatic activity
What is an important immunological factor for retaining tolerance to allergens?
Tregs
What are the possible diagnostics of IgE-mediated allergies? (4)
- Monoplex -> analysis of specific IgE through ELISA
- Functional -> basophil activation test
- Micro-array -> using a chip containing many allergens
- CLinical evaluations
Which clinical evaluations of IgE-mediated allergies are available? (2)
- Skin prick test
- Oral food challenge = gold standard
What are the treatment options of type I allergy?
- Elimination of allergen exposition
- Medication
- Specific immunotherapy
Which medications are (amongst others) available to treat type I allergic reactions? (2)
- Anti-histamines
- EpiPen
How does the specific immunotherapy for IgE-mediated allergies work?
Subcutaneous injection of escalating dosages of allergen, leading to Treg induction
What makes that coeliac disease is on the middle ground between an allergy and an auto-immune disease?
Allergic characteristic: triggered by relatively harmless exogenous antigen
Auto-immune characteristic: production of auto-antibodies
What is the treatment of coeliac disease?
Stopping gluten intake
What is the histopathological effect of coeliac disease?
Villus atrophy and flattening of the intestinal mucosa
Which HLA-genes are associated with coeliac disease? (2)
- HLA-DQ2.5
- HLA-DQ-8
Which component of gluten triggers coeliac disease? Why does this compound trigger a response?
Gliadin -> resistant to complete digestion by human digestive enzymes, partial digestion leads to large peptides. Tissue transglutaminase tries to break down these peptides, but instead creates an epitope that efficiently binds to HLA
What are the steps in coeliac disease pathogenesis?
- Gluten enter intestinal mucosa
- DCs/macrophages pick up deaminated gliadins -> presented to T-cells
- T-cells trigger a Th1-response
What is the standard diagnostic biomarker in blood for coeliac disease?
IgA anti-tTG
Which three things need to be evaluated for diagnosis of coeliac disease?
- Presence of coeliac disease-associated auto-antibodies
- HLA-typing (HLA-DQ2.5/HLA-DQ8)
- Duodenoscopy with biopsy
What are the differences between coeliac disease and wheat allergy? (4)
- Timing -> allergy = immediate, coeliac disease = over time
- Pathogenesis -> allergy = allergic reaction, coeliac disease = similar to auto-immune disease
- HLA-restriction -> allergy = not HLA-restricted, coeliac disease = HLA restricted
- Enteropathy -> absent in allergy, present in coeliac disease
What is a PID?
Primary immunodeficiency -> group of inherited disorders characterized by poor/absent function in one/more components of the immune system
What are clinical symptoms of PID? (7)
- Frequent and recurrent infections
- Inflammation and infection of internal organs
- Blood disorders (anaemia, thrombocytopenia)
- Digestive problems
- Delayed growth and development
- Auto-immune disorders
- Granuloma formation
What is the most important group of PID?
Antibody disorders
What is hypogammaglobulinaemia?
Immunoglobulins present, but too low
When do different gene defects lead to the same disease presentation in PIDs?
When they are part of the same signaling pathway
What is a functional test of BCR function? Which control is used?
Stimulating the BCR should lead to Ca2+-influx
-> if no Ca2+ influx -> dysfunctional BCR
Control: ionomycin -> opens Ca2+ channels to show that these channels are present
Which diagnostic processes need to be started in patients suspected of PID? (4)
- Clinical and immunological evaluation
- Flow cytometric immunophenotyping and functional studies of blood
- Molecular diagnostics of potentially mutated genes
- Genetic counseling and prenatal diagnotics by clinical genetics
What is a ‘typical’ presentation of primary antibody deficiencies?
Increased susceptibility to bacterial infections + agammaglobulinaemia/hypogammaglobulinaemia
What does a lack of pre-BCR signaling lead to?
Complete absence of B-cells -> agammaglobulinaemia
What are symptoms/characteristics of patients with agammagloblulinaemia? (3)
- Recurrent bacterial infections early in life
- Serum IgG very low (other Ig’s as well)
- Some present with overwhelming infection
What causes hyper-IgM diseases?
Defects in class switch recombination
What are the symptoms/characteristics of hyper-IgM diseases? (4)
- Recurrent bacterial and opportunistic infections
- Often pneumocystis jirovecii infection as presenting infection
- Neutropaenia
- Very low IgG, IgM can be low/normal/high
Which mutations can cause agammaglobulinaemia? (4)
Mutations in the pre-BCR signaling complex:
1. CD19
2. CD21
3. CD81
4. CD225
Mutations of which processes cause common variable immunodeficiency (CVID)? (3)
- Survival of B-cells
- Differentiation of B-cells into plasma cells
- Germinal centre formation
What is SCID?
Severe combined immunodeficiency -> either T-B- or T-B+
What are presenting features of SCID-patients? (3)
- Opportunistic infections
- Protracted diarrhoea
- Failure to thrive
What is the treatment of SCID?
Bone marrow transplantation
What causes T-B+ SCID? (3)
Mutations in genes required for T-cell development, such as:
1. IL-2R or IL-2 signal transduction -> necessary for T-cell development
2. IL7R -> necessary for T-cell survival
3. Mutations in CD3 -> prevents TCR signal transduction
Why does SCID often occur in boys?
Many genes that can cause SCID are X-linked
Which two forms of T-B- SCID are there? What causes them?
- Radiosensitive T-B- SCID -> defect in NHEJ, caused by mutations in Artemis
- Non-radiosensitive T-B- SCID -> defect in VDJ recombinatino, caused by RAG-mutations
Which three main types of haematological malignancy can be identified?
- Leukaemia
- Malignant lymphoma
- Multiple myleloma
Which subgroups of leukaemia are there? (2x2)
- Myeloid leukaemia
–Acute myeloid leukaemia
–Chronic myeloic leukaemia - Lymphoid leukaemia
–Acute lymphoid leukaemia -> common in children
–Chronic lymphoid leukaemia -> common in elderly
Which subgroups of malignant lymphoma are there? (2)
- Non-Hodkin lymphoma -> more common
- Hodgkin-lymphoma
What is often the most important pathogenic effect of haematological malignancies?
Suppression of the normal function of the immune system, leading to infections
When in the development process of immune cells do acute leukaemias develop?
Early development (bone marrow)
When in the development process of immune cells do lymphomas develop?
Later in development (lymphoid tissues)
When in the development process of immune cells do chronic leukaemias develop?
Later in development (circulation)
When in the development process of immune cells does multiple myeloma develop?
End-stage development (plasma cells)
What are B-cell Non-Hodgkin lymphomas caused by? What are three examples of this?
Translocation during gene rearrangement
1. Burkitt lymphoma -> caused by IGH enhancers being put before the MYC-gene ==> triggers rapid proliferation
2. Mantle cell lymphoma -> caused by IGH enhancers being put in front of Bcl1 ==> dysregulation of cell cycle
3. Follicular cell lympoma -> caused by IGH enhancers being put in front of Bcl2 ==> block of apoptosis
What is the location and clinical presentation (3) of acute leukaemia?
Location: bone marrow
Clinical presentation: bone marrow suppression
1. Anaemia
2. Thrombocytopenia
3. Granulopenia
What is the location and clincal presentation (3) of T-cell lymphoblastic lymphoma?
Location: cortex of the thymus
Clinical presentation:
1. Enlarged mediastinum
2. Enlarged lymph nodes
3. Leucocytosis
What is the location and clinical presentation (4) of chronic lymphocytic leukaemia?
Location: B-cell areas of lymphoid tissues, bone marrow & blood
Clinical presentation:
1. Leucocytosis
2. Lymphadenopathy
3. Symptoms at extranodal locations
4. Suppression of other cells in the blood
What is the location and clinical presentation (3) of multiple myeloma?
Location: bone marrow
Clinical presentation:
1. Bone lesions
2. Bone marrow suppression (anaemia, thrombocytopenia, granulopenia)
3. Increased sedimentation, monoclonal gammopathy
Why are B-cell lymphomas more common than T-cell lymphomas?
B-cells undergo more processes in which dsDNA-breaks occur:
1. VDJ-recombination (both T- and B-cells)
2. Somatic hypermutation (only B-cells)
3. Class switch recombination (only B-cells)
